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WO2025229120A1 - Dispositif de réaction en chaîne par polymérase, pcr, numérique, dispositif microfluidique, système, et procédé de chauffage d'un échantillon dans un dispositif de pcr numérique - Google Patents

Dispositif de réaction en chaîne par polymérase, pcr, numérique, dispositif microfluidique, système, et procédé de chauffage d'un échantillon dans un dispositif de pcr numérique

Info

Publication number
WO2025229120A1
WO2025229120A1 PCT/EP2025/061953 EP2025061953W WO2025229120A1 WO 2025229120 A1 WO2025229120 A1 WO 2025229120A1 EP 2025061953 W EP2025061953 W EP 2025061953W WO 2025229120 A1 WO2025229120 A1 WO 2025229120A1
Authority
WO
WIPO (PCT)
Prior art keywords
consumable
digital pcr
fluid
digital
heater
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/EP2025/061953
Other languages
English (en)
Inventor
Christopher Endres
Celia Francois
Sebastian SCHWAAK
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Qiagen GmbH
Original Assignee
Qiagen GmbH
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Qiagen GmbH filed Critical Qiagen GmbH
Publication of WO2025229120A1 publication Critical patent/WO2025229120A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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Classifications

    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L7/00—Heating or cooling apparatus; Heat insulating devices
    • B01L7/52—Heating or cooling apparatus; Heat insulating devices with provision for submitting samples to a predetermined sequence of different temperatures, e.g. for treating nucleic acid samples
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L3/00—Containers or dishes for laboratory use, e.g. laboratory glassware; Droppers
    • B01L3/50—Containers for the purpose of retaining a material to be analysed, e.g. test tubes
    • B01L3/502—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures
    • B01L3/5027—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip
    • B01L3/502715—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip characterised by interfacing components, e.g. fluidic, electrical, optical or mechanical interfaces
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L3/00—Containers or dishes for laboratory use, e.g. laboratory glassware; Droppers
    • B01L3/50—Containers for the purpose of retaining a material to be analysed, e.g. test tubes
    • B01L3/508—Containers for the purpose of retaining a material to be analysed, e.g. test tubes rigid containers not provided for above
    • B01L3/5085—Containers for the purpose of retaining a material to be analysed, e.g. test tubes rigid containers not provided for above for multiple samples, e.g. microtitration plates
    • B01L3/50851—Containers for the purpose of retaining a material to be analysed, e.g. test tubes rigid containers not provided for above for multiple samples, e.g. microtitration plates specially adapted for heating or cooling samples
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2200/00—Solutions for specific problems relating to chemical or physical laboratory apparatus
    • B01L2200/04—Exchange or ejection of cartridges, containers or reservoirs
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2200/00—Solutions for specific problems relating to chemical or physical laboratory apparatus
    • B01L2200/06—Fluid handling related problems
    • B01L2200/0689—Sealing
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2200/00—Solutions for specific problems relating to chemical or physical laboratory apparatus
    • B01L2200/10—Integrating sample preparation and analysis in single entity, e.g. lab-on-a-chip concept
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2300/00—Additional constructional details
    • B01L2300/06—Auxiliary integrated devices, integrated components
    • B01L2300/0627—Sensor or part of a sensor is integrated
    • B01L2300/0654—Lenses; Optical fibres
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2300/00—Additional constructional details
    • B01L2300/08—Geometry, shape and general structure
    • B01L2300/0809—Geometry, shape and general structure rectangular shaped
    • B01L2300/0829—Multi-well plates; Microtitration plates
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2300/00—Additional constructional details
    • B01L2300/08—Geometry, shape and general structure
    • B01L2300/0848—Specific forms of parts of containers
    • B01L2300/0851—Bottom walls
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2300/00—Additional constructional details
    • B01L2300/08—Geometry, shape and general structure
    • B01L2300/0861—Configuration of multiple channels and/or chambers in a single devices
    • B01L2300/088—Channel loops
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2300/00—Additional constructional details
    • B01L2300/18—Means for temperature control
    • B01L2300/1805—Conductive heating, heat from thermostatted solids is conducted to receptacles, e.g. heating plates, blocks
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2300/00—Additional constructional details
    • B01L2300/18—Means for temperature control
    • B01L2300/1838—Means for temperature control using fluid heat transfer medium
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2400/00—Moving or stopping fluids
    • B01L2400/04—Moving fluids with specific forces or mechanical means
    • B01L2400/0475—Moving fluids with specific forces or mechanical means specific mechanical means and fluid pressure
    • B01L2400/0487—Moving fluids with specific forces or mechanical means specific mechanical means and fluid pressure fluid pressure, pneumatics
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L3/00—Containers or dishes for laboratory use, e.g. laboratory glassware; Droppers
    • B01L3/50—Containers for the purpose of retaining a material to be analysed, e.g. test tubes
    • B01L3/502—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures
    • B01L3/5027—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip
    • B01L3/502761—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip specially adapted for handling suspended solids or molecules independently from the bulk fluid flow, e.g. for trapping or sorting beads, for physically stretching molecules
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L9/00—Supporting devices; Holding devices
    • B01L9/52—Supports specially adapted for flat sample carriers, e.g. for plates, slides, chips
    • B01L9/527—Supports specially adapted for flat sample carriers, e.g. for plates, slides, chips for microfluidic devices, e.g. used for lab-on-a-chip

Definitions

  • PCR polymerase chain reaction
  • PCR may be used to amplify the amount of a specific gene present in a sample, e.g., a DNA sample and/or an RNA sample, that may contain a number of different genes.
  • PCR can be used for a variety of experiments and/or analyses, including, e.g., genetic testing, forensic analyses, etc.
  • Variants of PCR may be used to quantitatively determine how much of a particular gene of interest is present within a sample of extracted DNA and/or RNA. This may be useful, for example, in determining whether the sample is heterozygous or homozygous for a specific gene of interest.
  • Digital PCR which is a known type of PCR, involves dividing a sample into a number, e.g., in particular a relatively large number, of separate aliquots. Some of the aliquots may contain a particular sequence, e.g., a DNA sequence and/or an RNA sequence, corresponding to a gene of interest and some of the aliquots may not contain the sequence of interest.
  • the aliquots may then be amplified to determine whether a molecule, e.g., a DNA molecule and/or an RNA molecule, containing the gene of interest is present within each aliquot. Based on the number of aliquots that have undergone exponential growth, the original concentration of DNA and/or RNA prior to dilution may be determined. Typically, this amplification includes heating and cooling the aliquots in a process called thermal cycling. During thermal cycling, the aliquots are heated to a preset specific temperature or a set of preset specific temperatures. The aliquots may be repeatedly heated using Peltier elements.
  • a contact surface of the consumable directed towards the Peltier element is not ideally flat and may include various shape irregularities.
  • the shape irregularities result in a nonuniform contact and causes losses in heat transfer over the surface of the consumable.
  • the consumable may be clamped to the Peltier element.
  • the consumable may still bend and the contact on a microstructure level may remain nonuniform due to an air gap between the thermocycler (e.g., the Peltier element) and the consumable.
  • the irregularities lead to an uneven heat transfer over the consumable.
  • Some consumables include micro-channels that are closed by a pressure activated transparent adhesive foil.
  • a specific clamping pressure is needed in order to prevent a liftoff of the pressure activated transparent adhesive file which would open the micro-channels between partitions of the plates. If the micro-channels between the partitions open, the aliquots contained in neighboring partitions may mix. This may occur in regions with no or incomplete contact between the consumable and the heating element.
  • a first aspect of the present disclosure relates to a digital polymerase chain reaction, PCR, device.
  • the device comprises a sample chamber, at least one heater and a pump.
  • the sample chamber is configured to hold at least one digital PCR consumable.
  • the at least one heater is configured to heat fluid to a set temperature.
  • the pump is configured for transporting the fluid from the heater to the sample chamber such that the heated fluid convectively heats the digital PCR consumable held in the sample chamber.
  • a polymerase chain reaction may be known as a reaction method that is used to quantify for example, nucleic acids by amplifying a nucleic acid molecule with the enzyme DNA polymerase.
  • Digital PCR involves dividing a sample into a number, e.g., in particular a relatively large number, of separate aliquots.
  • a consumable may be provided in order to prepare a, e.g., liquid, sample for dPCR and divide the sample into the separate aliquots.
  • the consumable may include a plurality of chambers, e.g., 8'500, 26'000 or more microchambers for each well.
  • the microchambers may be separated by a pressure activated transparent adhesive foil.
  • the consumable may comprise 10, 48, 96, 384 or more wells. Each of the wells may include 100, 8'500, 26'000, 760'000 or more microchambers.
  • An example consumable is a (microfluidic) device and/or the consumable may be a nanoplate or microplate.
  • the microfluidic device may be configured to comply with ANSI/SLAS microplate standards.
  • the microfluidic device may include one or more features, e.g., with respect to the microfluidic structure and/or the microfluidic channels, of the microfluidic device described in US 11,154,864 B2 and/or EP 2 969 215 Bl.
  • Digital polymerase chain reaction devices as required, e.g., in claim 1, may be understood as a device that is configured to cause a polymerase chain reaction in the aliquots of the consumable.
  • the device may have one or more of the following functions: filling the consumable with a sample, analyzing the consumable after heating, imaging the consumable, detecting properties of individual aliquots of the consumable.
  • the analysis of the consumable may be while and/or after heating (e.g. amplifying the DNA) the microfluidic device.
  • the sample chamber may be a closed or, in an alternative embodiment, open chamber.
  • the chamber is preferably enclosed by a housing.
  • Some digital PCR devices may include a sample chamber for holding one consumable, while other digital PCR devices may also hold more than one consumable e.g., two or four or eight or more (or anything in between).
  • the heater may be configured to heat a fluid, in particular a gas or a liquid, to a set temperature.
  • the fluid is a gas, and in particular air.
  • the temperature may be set by a user and may in some embodiments be part of a temperature profile.
  • the temperature profile may include multiple temperatures to which the fluid is heated. For example, first the fluid may be heated to a first set temperature and the consumable may be heated to the first temperature and, thereafter the fluid may be heated to a second set temperature and the consumable may be heated to the second temperature. Similarly, the fluid may be heated to a third, fourth, or fifth set temperature. In an embodiment the fluid may be preheated.
  • the temperature profile as mentioned herein refers to the temperature profile that may be required by a PCR protocol. An example PCR protocol involves cycling the sample through a set of two or more temperatures.
  • Heating as mentioned herein may refer to raising or maintaining a temperature above ambient.
  • a heating may encompass raising a temperature of a sample in a digital consumable from ambient to, e.g. 95°C (or any other temperature mentioned herein below). Heating may also encompass providing heated fluid to the consumable with the sample, wherein the heated fluid is less warm than the sample. For example, if the consumable with the sample was heated to 95°C (e.g. in a previous heating step) and heated fluid currently convectively heating the consumable with the sample has a temperature of 72°C, this may be considered as heating in the context of the present invention.
  • the digital PCR device may comprise a heater controller that is configured to control the temperature of the fluid currently heating the consumable.
  • the heater controller may be configured to follow a temperature profile as described herein.
  • the device may be configured to heat the consumable with fluid heated to a first temperature and thereafter to heat the consumable with fluid heated to a second set temperature.
  • the pump may transport the fluid from the heater to the sample chamber.
  • a pump as described herein may include any device suitable for moving the fluid towards the consumable.
  • the fluid from the heater that is moved by the pump may heat the digital PCR consumable held in the consumable and in the sample chamber convectively.
  • the consumable and the aliquots held therein may be evenly heated to the set temperature.
  • a precise fit between a surface of the consumable and a surface of the heater is not required. The fluid will reach all parts of the consumable leading to a uniform heating.
  • the device further comprises a consumable holder configured to hold the at least one digital PCR consumable in a position.
  • the consumable holder may be a tray.
  • the tray may, similarly to a tray of a Compact Disk, load the consumable into the sample chamber.
  • the tray may include a motor for moving the consumable into and out of the sample chamber.
  • the position may be fixed by including a form, fitting to the form of the at least one digital PCR consumable. In other embodiments, the position may be fixed using a clamp or similar devices. Since the digital PCR consumable is held in a known position, the heated fluid can be directed towards the consumable.
  • the pump may be configured for transporting the heated fluid to the position of the digital PCR consumable.
  • the pump may direct the heated fluid directly onto the consumable or the position of a consumable respectively.
  • the pump may direct the heated fluid onto the consumable, e.g., by including piping directed towards the consumable.
  • the digital PCR device is configured to form a closed fluid volume between a bottom side of the digital PCR consumable and the consumable holder. If a closed fluid volume is formed, the closed fluid volume can be set to have an overpressure.
  • the overpressure may be 300, 500, 700 or 1000 mbar above ambient.
  • an outlet of the closed fluid volume may include an overpressure valve (also described as pressure relief valve herein).
  • the overpressure valve may open when a pressure of 300, 500, 700 or 1000 mbar above ambient is exceeded.
  • the pressure within the closed volume may push a pressure activated adhesive foil that may be located at a bottom side of the consumable into the consumable, preventing microchambers in the consumable from reconnecting to each other.
  • a bottom side of the consumable as mentioned herein may refer to side opposing an inlet of the consumable and/or opposing an opening of some or all wells of the consumable.
  • a bottom side as mentioned herein may additionally or alternatively refer a side that points in the direction of gravity during proper handling of the consumable.
  • a bottom side may be put on a worksurface while filling the consumable with a sample.
  • the closed fluid volume comprises an inlet for receiving the heated fluid and outlet for expelling the heated fluid.
  • new fluid can be fed continuously into the closed fluid volume ensuring that the temperature within the closed fluid volume corresponds to the temperature of the fluid.
  • the device further comprises a pump controller configured to control the pump to maintain pressure above the ambient in the closed fluid volume.
  • the pump may be configured to create an overpressure of 300, 500, 700 or 1000 mbar above ambient. Thereby, the above-mentioned overpressure in the closed fluid volume can be created.
  • a closed fluid volume is advantageous as a smaller volume needs to be heated, the overpressure may also be instead created in the entire sample chamber.
  • the sample chamber may comprise a seal configured for sealing between the consumable holder and the consumable.
  • the seal further improves the heating as less fluid is lost.
  • the seal may be a rubber seal, onto which the consumable may be pressed.
  • a heater control may be configured to control the heater to heat the fluid to a temperature of 50, 55, 58, 62, 70, 72, 80, 90, 95°C or more and/or configured to cycle between a set of two, three or more temperatures according to a temperature profile.
  • the fluid supplied to the consumable may cycle between a set of two, three or more temperatures according to a temperature profile.
  • the temperature, to which the fluid is heated may be in the range of 30°C to 100°C. The temperatures may depend on the desired PCR reaction. Thus, the presently disclosed device is particularly suitable for PCR reactions.
  • the device may comprise a temperature sensor.
  • the temperature sensor may be configured to measure a temperature of the fluid.
  • the temperature sensor may be configured to measure the temperature of the fluid at the heater, in the closed fluid volume, at an inlet or outlet of the closed fluid volume, in one or more fluid containers holding a heated fluid or in fluid channels guiding the heated fluid.
  • more than one or each of these may comprise a respective temperature sensor.
  • at least the closed fluid volume comprises a temperature sensor.
  • the temperature sensor allows for precisely controlling the temperature of the heated fluid. As dPCR is sensitive to temperature fluctuations, controlling the temperature more precisely allows for a more precise dPCR.
  • the pump may be arranged upstream or downstream of the heater.
  • the pump being arranged upstream of the heater has the advantage, that there is less pressure loss along the transport means, e.g., a piping.
  • the pump being arranged downstream of the heater has the advantage that the pump can transport air prior to heating reducing tear and wear on the pump.
  • the heater may be an electrical heater and may include at least one heat transfer element.
  • the heater is an electrical heater and may comprise a heating wire that is exposed to a flow of fluid, in particular air. Any electrical heater that is suitable to heat liquids or fluids may be used.
  • Example heaters may include Peltier elements, duct heaters, enclosure heaters, forced air heaters, and tubular heaters.
  • the at least one heater may be a flow heater. Alternatively (or additionally) to a flow heater, the at least one heater may be configured to heat fluid stored in one or more containers. Each container may include a heater.
  • the device may further comprise at least one heated fluid chamber for storing heated fluid having a set temperature.
  • the device may heat and store fluid in the fluid chamber. Once the consumable is to be heated, the fluid can be removed from the chamber, e.g., using the pump. Thus, a smaller heater can be used as the air can be heated over a longer amount of time.
  • the device may comprise at least two, preferably three heated fluid chambers for storing fluid with a set temperature.
  • the set temperature in each of the at least two, preferably three, heated fluid chambers may be different.
  • a thermocycler may include cycling between two or more temperatures.
  • the device comprising at least two, preferably three, heated fluid chambers has the advantage, that fluid heated to a certain temperature can be provided quickly and without delay.
  • the consumable holder may comprise a bottom opening such that at least a bottom side of the digital PCR consumable is exposed when held in the consumable holder. Thereby, a sample held within the consumable can be efficiently heated.
  • the consumable holder may comprise a clamp.
  • the clamp may comprise a clamping plate.
  • the clamp may be configured to clamp the digital PCR consumable in the preferably fixed position. Thereby, it may be ensured that the digital PCR consumable maintains its position when the fluid convectively hits the digital PCR consumable.
  • the clamps may be located on a top side of the digital PCR holder. This is particular efficient in terms of space as the bottom portion is preferably exposed to the heated fluid.
  • the consumable holder may comprise a tray for holding the digital PCR consumable.
  • the tray may include a bottom opening and a seal for sealing between a bottom side of the digital PCR consumable and the tray. This is a convenient arrangement for a user. The user simply needs to insert the consumable into the consumable holder, i.e., the tray and the consumable is accurately positioned for being heated.
  • the device may further comprise a camera that is configured to image at least a portion of a bottom portion of the digital PCR consumable.
  • the camera may also be configured to image the entire bottom portion of the digital PCR consumable.
  • the device may further comprise an optically transparent material that is arranged between the camera and the sample chamber.
  • the optically transparent material may form a wall of the closed fluid volume mentioned above.
  • the optically transparent material allows forming a sample chamber while at the same time allowing digital imaging using the above-mentioned camera. This enables a real-time digital PCR. Heating equipment that requires direct contact such as Peltier elements, or (other) cooling bodies, etc. is not needed.
  • the consumable can be observed without having to remove the consumable from a heating position, simplifying the handling within the device.
  • the camera may be arranged in a pressurized chamber.
  • the pressurized chamber may be adjacent the closed fluid volume and a wall separating the closed fluid volume and the pressurized chamber is made of the optically transparent material.
  • the optically transparent material e.g., an optical glass, may seal between the consumable.
  • the sample chamber may be formed between the consumable and the optically transparent material.
  • a pressure in the pressurized chamber may be higher than a pressure in the closed fluid volume.
  • the pressurized chamber may comprise a pressure relief valve.
  • the pressure relief valve may be configured to set a pressure to a predetermined value. Example values are mentioned above.
  • the optically transparent material may define a portion of the closed fluid volume. Thereby, the consumable can be observed in real time while heating the consumable convectively.
  • the optically transparent material may define a bottom wall of the closed fluid volume.
  • the pump may include at least one of: a fan, a centrifugal pump, a rotary pump, and a piston pump. Thereby, the fluid can be transported from the heater to the consumable.
  • the consumable holder may include a tray with a bottom opening.
  • the bottom opening may expose a bottom portion of the digital PCR consumable.
  • the heated fluid may be transported through the bottom opening.
  • a further aspect of the present disclosure relates to a microfluidic device configured for digital polymerized chain reaction, PCR.
  • the device comprises a housing, a foil, and an outer seal.
  • the housing forms a plurality of microfluidic chambers and may include one or more channels connecting the microfluidic chambers.
  • the foil is arranged on a bottom side of the device and seals at least one channel and/or microfluidic chamber of the microfluidic device.
  • the outer seal at the bottom is configured for providing a closed fluid volume between at least a portion of the bottom side of the device and a consumable holder of a digital polymerized chain reaction, digital PCR, device.
  • the digital PCR device may be a device as described above.
  • the seal may in particular be made of rubber or silicone.
  • a sealing between a microfluidic device, e.g., a consumable as described above, and a digital PCR device may be improved. Further, the sealing becomes part of a consumable and thus does not need to be replaced within the digital PCR device described above.
  • the seal may extend along an outer edge of the bottom side of the microfluidic device.
  • the foil may be a pressure activated adhesive foil.
  • Pressure activated adhesive foils are particularly suitable for separating microfluidic chambers, as the microfluidic chambers may be separated by pressing the adhesive foil against the microfluidic device.
  • a further aspect of the present disclosure relates to a system or set comprising a digital polymerase chain reaction device as described above and a consumable, preferably a microfluidic device as described above.
  • a further aspect of the present disclosure relates to a method of heating a sample in a digital polymerase chain reaction, PCR, device.
  • the method comprises the following steps: a digital PCR consumable is obtained.
  • the consumable may be a consumable as described above.
  • the digital PCR consumable is inserted into a sample chamber.
  • the sample chamber is configured to hold the digital PCR consumable.
  • a fluid is heated with a heater to a set first temperature.
  • the heated fluid is provided from the heater to the digital PCR consumable.
  • the heated fluid heats the digital PCR consumable with the fluid convectively to the first temperature. This may heat the sample, e.g. the liquid, within the consumable to the set first temperature.
  • a closed volume may be formed between a bottom side of the digital PCR consumable and the consumable holder.
  • the heated fluid is provided into the closed fluid volume, i.e., transported into the closed fluid volume.
  • a pump may generate an overpressure in the closed fluid volume in order to prevent a lift-off of a pressure adhesive foil on the digital PCR consumable.
  • the closed volume may have the advantage that not the entire digital PCR device needs to be heated but rather only a small volume below the PCR consumable.
  • providing the heated fluid into the closed fluid volume may comprise pumping the heated fluid into the closed fluid volume with a pump.
  • the method may further comprise controlling the pump with a pump controller such that a pressure above an ambient pressure in the closed fluid volume is maintained in the closed fluid volume.
  • the closed fluid volume may include an overpressure valve, that releases air once a preset pressure above ambient is achieved.
  • the method may comprise the step of heating a fluid with a heater to a set second temperature and providing the heated fluid from the heater to the digital PCR consumable and convectively heating at least one side of the digital PCR consumable with the fluid to the second temperature.
  • This may heat the sample, e.g. the liquid, within the consumable to the set second temperature.
  • the heated fluid may heat the sample (e.g. liquid) in the consumable entirely to the first or second (or other) temperature by convectively heating one side of the consumable.
  • a temperature profile is achieved according to which the consumable is heated to different temperatures according to e.g., a thermal cycling as provided in PCR.
  • the digital PCR device may also encompass a controller configured to follow one or more of temperature profiles mentioned herein.
  • the method may comprise further steps of heating a fluid with the heater to a set third, fourth, fifth and/or further set temperatures and providing the heated fluid from the heater to the digital PCR consumable and convectively heating at least one side of the digital PCR consumable with the fluid to the respective set temperature.
  • the second temperature may be higher or lower than the first temperature.
  • Heating as mentioned herein may refer to a temperature that is higher than the ambient temperature. Different heating steps may include different temperature and each temperature can be higher or lower than the previous temperature. Heating is mentioned herein may also comprise maintaining the consumable at a lower than previous although higher than ambient temperature.
  • the method may comprise the step of cyclically repeating the heating and providing steps for the first and second temperatures.
  • the third, fourth, fifth and/or further set temperatures and providing heated fluid accordingly may also be cyclically repeated.
  • the present disclosure is not restricted to any particular temperature profile.
  • the method may comprise the step of capturing an image of at least a portion of the digital consumable with a camera.
  • the image may be captured while convectively heating the digital PCR consumable.
  • the step of capturing the image may comprise one image of all aliquots held within the consumable or may also comprise capturing multiple images each containing a portion of the aliquots held within the consumable.
  • the present disclosure allows capturing images while still heating the consumable enabling a real-time capturing of the digital PCR.
  • an optically transparent material may be provided between the camera and the portion of the digital PCR consumable, preferably the bottom portion of the digital PCR consumable.
  • Digital polymerase chain reaction, PCR, device comprising: a sample chamber, the sample chamber being configured to hold at least one digital PCR consumable; at least one heater, the heater being configured to heat a fluid to a set temperature; and a pump configured for transporting the fluid from the heater to the sample chamber such that the heated fluid convectively heats the digital PCR consumable held in the sample chamber.
  • Digital PCR device according to aspect 1, further comprising: a consumable holder configured to hold the at least one digital PCR consumable in a, preferably fixed, position, wherein the pump is configured for transporting the heated fluid to the position of the digital PCR consumable.
  • Digital PCR device configured to form a closed fluid volume between a bottom side of the digital PCR consumable and the consumable holder.
  • Digital PCR device according to aspect 3, wherein the closed fluid volume comprises an inlet for receiving the heated fluid and an outlet for expelling the heated fluid.
  • Digital PCR device according to aspect 3 or 4, further comprising: a pump controller configured to control the pump to maintain a pressure above ambient in the closed fluid volume.
  • Digital PCR device according to any one of aspects 2 to 5, wherein the sample chamber comprises a seal configured for sealing between the consumable holder and the digital PCR consumable.
  • Digital PCR device according to any one of aspects 1 to 6, further comprising: a heater controller configured to control the heater to heat the fluid to a temperature of 50, 55, 58, 62, 70, 72, 80, 90, 95°C or more and/or configured to cycle between a set of two, three or more temperatures according to a temperature profile.
  • Digital PCR device according to any one of aspects 1 to 7, wherein the fluid is a gas, preferably air.
  • Digital PCR device according to any one of aspects 1 to 8 wherein the pump is arranged upstream or downstream of the heater.
  • the heater is an electrical heater and preferably includes at least one heat transfer element, and more preferably the heat transfer element including a resistive heating element and being configured to direct a flow of fluid towards the resistive heating element.
  • Digital PCR device according to any one of aspects I to 10, further comprising: at least one heated fluid chamber for storing heated fluid having a set temperature.
  • Digital PCR device further comprising: at least two, preferably three, heated fluid chambers for storing fluid with a set temperature, wherein the set temperature in each of the at least two, preferably three, heated fluid chambers is different.
  • Digital PCR device according to any one of aspects 2 to 12, wherein the consumable holder comprises a bottom opening such that at least a bottom side of the digital PCR consumable is exposed when held in the consumable holder.
  • Digital PCR device according to any one of aspects 2 to 13, wherein the consumable holder comprises a clamp, preferably comprising a clamping plate, the clamp being configured to clamp the digital PCR consumable in the, preferably fixed, position.
  • Digital PCR device according to aspect 14, wherein the clamp is located on a top side of the digital PCR holder.
  • the consumable holder comprises a tray for holding the digital PCR consumable, the tray including a bottom opening and a seal for sealing between a bottom side of the digital PCR consumable and the tray.
  • Digital PCR device according to any one of aspects I to 16, further comprising: a camera configured to image at least a portion of a bottom portion of the digital PCR consumable.
  • Digital PCR device further comprising: an optically transparent material, the optically transparent material being arranged between the camera and the sample chamber.
  • Digital PCR device when dependent on aspect 3, wherein the camera is arranged in a pressurized chamber, wherein the pressurized chamber is adjacent the closed fluid volume and a wall separating the closed fluid volume and the pressurized chamber is made of the optically transparent material.
  • Digital PCR device according to aspects 3 and/or 19, wherein the closed fluid volume and/or the pressurized chamber comprise(s) a pressure relief valve.
  • Digital PCR device according to any one of aspects 18 to 20 when dependent on aspect 3, wherein the optically transparent material defines a portion of the closed fluid volume.
  • Digital PCR device according to any one of aspects 1 to 21, wherein the pump includes at least one of: a fan, a centrifugal pump, a rotary pump, and a piston pump.
  • Digital PCR device according to any one of aspects 2 to 22, wherein the consumable holder includes a tray with a bottom opening for exposing a bottom portion of the digital PCR consumable and wherein the heated fluid is transported through the bottom opening.
  • Microfluidic device configured for digital polymerase chain reaction, PCR, comprising, a housing forming a plurality of microfluidic chambers and/or including one or more channels; a foil, wherein the foil is arranged on a bottom side of the device and wherein the foil seals at least one channel and/or microfluidic chamber of the microfluidic device; an outer seal arranged at a bottom portion of the device configured for providing a closed fluid volume between at least a portion of the bottom side of the device and a consumable holder of a digital polymerase chain reaction, digital PCR, device, preferably a digital PCR device according to any one of aspects 1 to 23. 25. Microfluidic device according to aspect 24, wherein the foil is a pressure activated adhesive foil.
  • System or set comprising a digital polymerase chain reaction, PCR, device according to any one of aspects 1 to 23 and a digital PCR consumable, preferably a microfluidic device according to aspect 24 or 25.
  • Method of heating a sample in a digital polymerase chain reaction, PCR device comprising the steps of: obtaining a digital PCR consumable, preferably a microfluidic device according to aspect 24 or 25; inserting the digital PCR consumable in a sample chamber, the sample chamber being configured to hold the digital PCR consumable; heating a fluid with a heater to a set first temperature; and providing the heated fluid from the heater to the digital PCR consumable and convectively heating at least one side of the digital PCR consumable and in particular the sample with the fluid to the first temperature.
  • Method of aspect 27 comprising the steps of: forming a closed fluid volume between a bottom side of the digital PCR consumable and the consumable holder; and providing the heated fluid into the closed fluid volume.
  • Method of aspect T1 or 28 wherein providing the heated fluid into the closed fluid volume comprises pumping the heated fluid into the closed fluid volume with a pump and the method further comprises controlling the pump with a pump controller such that a pressure above ambient is maintained in the closed fluid volume.
  • Method of any one of aspects 27 to 29, comprising the steps of: heating a fluid with a heater to a set second temperature; and providing the heated fluid from the heater to the digital PCR consumable and convectively heating at least one side of the digital PCR consumable with the fluid to the second temperature.
  • Method of aspect 30, comprising the step of: cyclically repeating the heating and providing steps for the first and second temperatures.
  • Method of one of the aspects 28 to 31, comprising the step of: capturing an image of a at least a portion of the digital PCR consumable with a camera while convectively heating the digital PCR consumable and in particular the sample in the consumable.
  • Method of aspect 32 comprising the step of: providing an optically transparent material between the camera and the portion of the digital PCR consumable.
  • Fig. 1 shows, in a perspective view, an example digital PCR device
  • Fig. 2 figure shows, in a perspective view, a thermocycler within the digital PCR device shown in figure 1 in isolation;
  • Fig. 3 shows, in a schematic view, a digital PCR consumable with a heating arrangement of the digital PCR device shown in figure 1; and Fig. 4 shows, in a schematic view a digital PCR consumable with a heating arrangement according to the present disclosure.
  • Figure 1 shows a digital PCR device 1.
  • An example digital PCR device is the QIACuity manufactured by the present applicant.
  • the digital PCR device includes a display 2 for a user for interacting with the device and a tray 3 for inserting digital PCR consumables 4 (see e.g., figure 3).
  • the digital PCR device 1 may be a tabletop device.
  • the digital PCR device 1 may be suitable to be placed on a lab bench.
  • the digital PCR device 1 includes an outer housing 5 that covers the device.
  • FIG. 2 shows a thermocycler 100 of the digital PCR device 1.
  • the thermocycler 100 is an internal component of the digital PCR device 1.
  • the thermocycler 100 includes an alloy plate 9 for heating consumables 4. Above the alloy plate 9, a sample chamber 36 is formed. Consumables 4 that are inserted into the tray 3 (see figure 1) and drawn into the digital PCR device 1 with the tray 3. Within the digital PCR device 1, a consumable 4 may transported to the thermocycler 100.
  • the digital PCR device 1 may comprises a transport device (e.g. a gripper or belt) that moves the consumable from the tray 3 to the thermocycler 100.
  • a transport device e.g. a gripper or belt
  • the consumable 4 is moved into the sample chamber 36 and can be heated with the heater 6. This is schematically shown in figure 3.
  • FIG 3 shows a consumable 4.
  • the consumable 4 includes a top seal 7 and a microplate.
  • the consumable 4 shown in figure 3 is the microfluidic device disclosed in in US 11,154,864 B2 and/or EP 2 969 215 Bl.
  • the consumable 4 includes a bottom side with a bottom seal, as e.g., described in US 11,154,864 B2 with reference to figures 17A and 17B.
  • the bottom seal may block off microfluidic channels between microfluidic chambers to isolate fluid samples held by each microchamber, i.e., the above-mentioned aliquots.
  • the consumable 4 when held in sample chamber 36 in thermocycler 100 and inside of the digital PCR device 1, is arranged close to the heaters 6 (e.g., Peltier elements). On top of the Peltier elements, an alloy plate 9 is arranged which conducts heat. Further, there is a gap pad 8 between the alloy plate 9 and the consumable 4. The alloy plate 9 and the gap pad 8 introduce thermal resistance between the Peltier elements and the consumable. Further, a contact between the gap pad 8 and the consumable 4 may be nonuniform, leading to nonuniform heating and to the possibility of the bottom seal detaching and microfluidic chambers undesirably connecting.
  • the heaters 6 e.g., Peltier elements
  • an alloy plate 9 is arranged which conducts heat. Further, there is a gap pad 8 between the alloy plate 9 and the consumable 4.
  • the alloy plate 9 and the gap pad 8 introduce thermal resistance between the Peltier elements and the consumable. Further, a contact between the gap pad 8 and the consumable 4 may be nonuniform, leading to
  • Figure 4 shows an arrangement for heating the consumable 4 according to the present disclosure.
  • the consumable 4 is not in direct contact with a gap pad.
  • a closed fluid volume 20 is formed below the consumable 4.
  • the closed fluid volume 20 formed between the consumable 4 and an optical glass 21.
  • the closed fluid volume 20 includes an inlet 34 and an outlet 22.
  • the inlet 34 is connected to piping 23.
  • the piping 23 connects to three different heat transfer elements 24, 25, and 26. Though the embodiment shows three heat transfer elements, any number (e.g., 1, 2, 4, 5, etc.) of heat transfer elements may be used. Heat transfer elements are also described as heaters herein.
  • Each heat transfer element is, as indicated in figure 4 adapted to heat a flow of air (or another fluid) passing the heat transfer element to a preset temperature.
  • the heat transfer element 24 is adapted to heat the flow of air to 60°C
  • heat transfer element 25 is adapted to heat the flow of air to 72°C
  • the heat transfer element 26 is adapted to heat a flow of air passing the heat transfer element to 95°C.
  • the device may comprise a container for holding the fluid that was heated to a respective set temperature (i.e., a heated fluid chamber).
  • a container for holding the fluid that was heated to a respective set temperature i.e., a heated fluid chamber.
  • a container for holding the fluid i.e., a heated fluid chamber.
  • a first container 24a in which air heated to e.g. 60°C is stored, e.g., after it was heated by heat transfer element 24.
  • a second container 25a in which air heated to e.g. 72°C is stored, e.g., after it was heated by heat transfer element 25 and/or a third container 26a in which air heated to e.g. 95°C is stored, e.g., after it was heated by heat transfer element 26.
  • the heat transfer elements may be part of the container for holding the fluid.
  • the fluid could be heated in advance to the set temperature and then be released when needed.
  • air is used to transfer heat from the heat transfer elements to the consumable 4.
  • any other fluid i.e., liquid or gas, may be used to transfer heat from the heat transfer elements to the consumable 4.
  • the flow of air is caused by a pump J that is arranged upstream of the heat transfer element.
  • the pump draws its airflow from the closed fluid volume 20 using further piping 28.
  • a closed loop of fluid flow is formed.
  • the heated air is directed into the closed fluid volume 20.
  • the heated air convectively heats the digital PCR consumable. Heating the consumable 4 with a fluid according to the disclosure has the advantage, that the consumable 4 is evenly heated.
  • the consumable 4 may be heated using the fluid heated to different temperatures in sequence.
  • fluid from the heat transfer element 24 may transported to the consumable 4 to convectively heat the consumable. While fluid from the heat transfer element 24 may transported to the consumable 4, no fluid may be transported from the other heat transfer elements 25 and 26.
  • fluid from the heat transfer element 25 may be transported to the to the consumable 4 to convectively heat the consumable. While fluid from the heat transfer element 24 may transported to the consumable 4, no fluid may be transported from the other heat transfer elements 24 and 26.
  • fluid from the heat transfer element 26 may be transported to the to the consumable 4 to convectively heat the consumable.
  • While fluid from the heat transfer element 26 may transported to the consumable 4, no fluid may be transported from the other heat transfer elements 25 and 26.
  • the transport may be achieved through valves (not shown) in the piping connecting the heat transfer elements 24 to 26 and/or valves (not shown) at outlets of containers 24a to 26a.
  • PCR may require a temperature profile. Switching between the fluids heated to different temperatures may change the temperature of the fluid transported to the consumable 4, thereby following the temperature profile.
  • the single heat transfer element or each of the heat transfer elements 24 to 26 is a flow heater.
  • one heater transfer element may be arranged upstream of the containers 24a to 26a and the device may be configured to supply heated fluid from the one heat transfer element at a first temperature to the first container 24, at a second temperature to the second container 25, and at a third temperature to the third container 26.
  • the fluid stored in the containers 24 to 26 at different temperatures may be released in accordance to the temperature profile as described above. More generally, the fluid heated by one heat transfer element may be stored in one or more containers and released when needed.
  • the number of containers may be based on the number temperature levels in a temperature profile. In one example, there may be one container for each temperature level. In another embodiment, there may be less containers than temperature levels.
  • the device 1 may additionally comprise a clamping plate 33 (see also figure 2).
  • the clamping plate 33 presses the consumable 4 against the optical glass 21.
  • the clamping plate 33 and the optical glass 21 may individually or jointly form a consumable holder.
  • a element 33 is preferably a clamping plate, it may also be a clamping element without necessarily being plate shaped. This ensures that the closed fluid volume 20 is closed and the heated fluid remains within the closed fluid volume 20.
  • the embodiments show that the closed fluid volume 20 is limited by a bottom side of the consumable 4 and the optical glass 21, other configurations are possible (although some of the advantages disclosed herein may not be achieved). For example, there may be no closed fluid volume 20 and the entire sample chamber 36 may be heated.
  • Heating the consumable 4 may cause the bottom seal to detach.
  • the closed fluid volume 20 may be maintained at a pressure above ambient, e.g., 1 bar above ambient.
  • the sample chamber may include a sealing 29.
  • the sealing 29, e.g., a pliant and soft materials such as rubber or silicone may be part of the consumable 4 or the clamping plate 33 of sample chamber 36 or the optical glass 21.
  • the sealing 29 seals between a frame of the consumable 4 and the optical glass 21. This ensures that the overpressure in the closed fluid volume 20 can be maintained.
  • the device 1 includes a camera module 30.
  • the camera module 30 is configured to image a bottom side of the consumable 4. From the bottom side, the microchambers of the consumable 4 can be observed. These microchambers may, depending on the chemical and biological contents of the microchamber, exhibit a luminance which may be recorded by the camera 30. As can be seen from figure 4, the camera 30 is positioned to record a bottom side of the consumable 4. Due to the optical glass 21 (or any other optically transparent material), the camera 30 can observe microchambers within the consumable 4 in real-time. In addition, the consumable 4 does not have to be removed from the position in which it is heated for evaluation of the microchambers.
  • the camera module 30 may be arranged in a second closed fluid volume 35 that is also exposed to an overpressure.
  • the second closed chamber may include an overpressure release vent 31 and the second closed chamber may be connected to the same (or a different) pump 27 with second pressure chamber tubing 32.
  • the overpressure release vent may be set to release pressure soon as an overpressure of, e.g., 1 bar, is achieved within the second closed chamber.

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Abstract

La présente divulgation se rapporte à un dispositif de réaction en chaîne par polymérase, PCR, numérique. Le dispositif comprend une chambre d'échantillon (36), au moins un dispositif de chauffage (24, 25, 25) et une pompe (27). La chambre d'échantillon est conçue pour contenir au moins un consommable de PCR numérique. Le ou les dispositifs de chauffage sont conçus pour chauffer un fluide à une température définie. La pompe est conçue pour transporter le fluide du dispositif de chauffage à la chambre d'échantillon de telle sorte que le fluide chauffé chauffe par convection le consommable de PCR numérique contenu dans la chambre d'échantillon.
PCT/EP2025/061953 2024-04-30 2025-04-30 Dispositif de réaction en chaîne par polymérase, pcr, numérique, dispositif microfluidique, système, et procédé de chauffage d'un échantillon dans un dispositif de pcr numérique Pending WO2025229120A1 (fr)

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EP24173522.4 2024-04-30

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US20030150982A1 (en) * 2002-02-08 2003-08-14 Eppendorf Ag Covering for the apertures of reaction receptacles constituted in microtitration plates
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US20090162928A1 (en) * 2002-12-19 2009-06-25 3M Innovative Properties Company Integrated sample processing devices
US20120115189A1 (en) * 2007-02-05 2012-05-10 IntegenX, Inc. Microfluidic and nanofluidic devices, systems, and applications
EP2969215B1 (fr) 2013-03-14 2019-09-18 QIAGEN Sciences, LLC Dispositif microfluidique
AU2020273294A1 (en) * 2017-08-29 2020-12-17 Bio-Rad Laboratories, Inc. System and Method for Isolating and Analyzing Cells
US11154864B2 (en) 2018-01-17 2021-10-26 Qiagen Sciences, Llc Microfluidic device with vented microchambers
US20230022568A1 (en) * 2021-07-23 2023-01-26 Nokia Technologies Oy Apparatus and Electronic Device for Analysing Samples

Patent Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20060011478A1 (en) * 1999-07-28 2006-01-19 Serono Genetics Institute S.A. Integration of biochemical protocols in a continuous flow microfluidic device
US20030150982A1 (en) * 2002-02-08 2003-08-14 Eppendorf Ag Covering for the apertures of reaction receptacles constituted in microtitration plates
US20090162928A1 (en) * 2002-12-19 2009-06-25 3M Innovative Properties Company Integrated sample processing devices
US20060233670A1 (en) * 2003-09-19 2006-10-19 Lehto Dennis A High density plate filler
US20120115189A1 (en) * 2007-02-05 2012-05-10 IntegenX, Inc. Microfluidic and nanofluidic devices, systems, and applications
EP2969215B1 (fr) 2013-03-14 2019-09-18 QIAGEN Sciences, LLC Dispositif microfluidique
AU2020273294A1 (en) * 2017-08-29 2020-12-17 Bio-Rad Laboratories, Inc. System and Method for Isolating and Analyzing Cells
US11154864B2 (en) 2018-01-17 2021-10-26 Qiagen Sciences, Llc Microfluidic device with vented microchambers
US20230022568A1 (en) * 2021-07-23 2023-01-26 Nokia Technologies Oy Apparatus and Electronic Device for Analysing Samples

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